{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T16:20:05Z","timestamp":1789402805673,"version":"build-2803163510"},"reference-count":33,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T00:00:00Z","timestamp":1765584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Ovarian neuroendocrine neoplasms (O-NENs) are extremely rare, representing less than 1% of all ovarian neoplasms and under 5% of all neuroendocrine tumors (NETs). They encompass two primary histological subtypes: well-differentiated carcinoids and poorly differentiated neuroendocrine carcinomas, which display distinct biological behaviors and prognoses. The ovary can also be a site of metastasis from extra-ovarian NETs. Owing to their rarity, clinical management lacks standardization, and diagnosis is often incidental following surgery for presumed epithelial ovarian neoplasms. Objectives: This review aims to provide an updated synthesis of current evidence on the epidemiology, pathogenesis, clinical presentation, diagnosis, treatment strategies, and prognosis of O-NENs, highlighting unmet clinical needs. Methods: A literature search was performed on PubMed for the years 2014\u20132024 using the keywords: \u201covarian neuroendocrine tumor\u201d, \u201covarian neuroendocrine neoplasm\u201d, \u201covarian neuroendocrine carcinoma\u201d, and \u201covarian carcinoid\u201d. Only articles published in English were considered. Given the rarity of the disease, in addition to meta-analyses and systematic reviews, relevant case reports and case series were also included to provide a comprehensive clinical picture, yielding 32 eligible articles. Results: Evidence indicates that O-NENs remain understudied, with most data derived from case reports and small series. Clinical presentations vary from asymptomatic masses to hormone-related syndromes, often mimicking other ovarian pathologies. Diagnostic work-up typically follows the same protocol as epithelial ovarian cancer, with the neuroendocrine nature only recognized postoperatively. Treatment strategies are empirical and largely extrapolated from extra-ovarian NETs due to the absence of specific guidelines. Prognosis varies widely depending on histotype, stage, and secretory activity. Conclusions: O-NENs pose significant diagnostic and therapeutic challenges due to their rarity and heterogeneity. Greater clinical awareness, multidisciplinary management, and multicenter research are essential to establish evidence-based protocols and improve patient outcomes.<\/jats:p>","DOI":"10.3390\/jcm14248833","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T09:57:24Z","timestamp":1765879044000},"page":"8833","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ovarian Neuroendocrine Neoplasms: Challenges and Future Perspectives"],"prefix":"10.3390","volume":"14","author":[{"given":"Valentina","family":"Di Vito","sequence":"first","affiliation":[{"name":"Department of Endocrinology, San Camillo-Forlanini Hospital, 00152 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8653-3694","authenticated-orcid":false,"given":"Gabriele","family":"Veroi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, San Camillo-Forlanini Hospital, 00152 Rome, Italy"},{"name":"Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rizza","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, San Camillo-Forlanini Hospital, 00152 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Rota","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, San Camillo-Forlanini Hospital, 00152 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Baiocchini","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology, San Camillo-Forlanini Hospital, 00152 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4199-5636","authenticated-orcid":false,"given":"Maria Cristina","family":"Macciomei","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology, San Camillo-Forlanini Hospital, 00152 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8261-1451","authenticated-orcid":false,"given":"Carla","family":"Lubrano","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5020-8657","authenticated-orcid":false,"given":"Anna","family":"La Salvia","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, National Institute of Health (ISS), 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Lania","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetology and Andrology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia Rosalba","family":"Grillo","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology, San Camillo-Forlanini Hospital, 00152 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4563-6630","authenticated-orcid":false,"given":"Silvia","family":"Migliaccio","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Rindi","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Baldelli","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, San Camillo-Forlanini Hospital, 00152 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S35","DOI":"10.1097\/IGC.0000000000000265","article-title":"Gynecologic Cancer InterGroup (GCIG) Consensus Review for Carcinoid Tumors of the Ovary","volume":"24","author":"Reed","year":"2014","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Virarkar, M., Vulasala, S.S., Morani, A.C., Waters, R., Gopireddy, D.R., Kumar, S., Bhosale, P., and Lall, C. (2022). Neuroendocrine Neoplasms of the Gynecologic Tract. Cancers, 14.","DOI":"10.3390\/cancers14071835"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s12032-024-02544-w","article-title":"Clinicopathologic Feature and Treatment Progress of High-Grade Ovarian Neuroendocrine Tumors","volume":"42","author":"He","year":"2024","journal-title":"Med. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"396","DOI":"10.4103\/IJPM.IJPM_232_16","article-title":"Bilateral Ovarian Metastases as the Presenting Manifestation of Lung Carcinoid in a 50-Year-Old Woman: Case Study and Review of Literature","volume":"60","author":"Mitra","year":"2017","journal-title":"Indian J. Pathol. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.tjog.2015.05.008","article-title":"Rare Case of Primary Trabecular Carcinoid Tumor of the Ovary with Unusual Presentation","volume":"55","author":"Sharma","year":"2016","journal-title":"Taiwan. J. Obstet. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s11912-017-0617-2","article-title":"Pathology of Neuroendocrine Tumours of the Female Genital Tract","volume":"19","author":"Howitt","year":"2017","journal-title":"Curr. Oncol. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e21109","DOI":"10.1097\/MD.0000000000021109","article-title":"Primary Ovarian Carcinoid: Two Cases Report and Review of Literature","volume":"99","author":"Zhai","year":"2020","journal-title":"Medicine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5053","DOI":"10.21873\/anticanres.13697","article-title":"Metastatic Bilateral Strumal Carcinoid: A Case Report and Review of the Literature","volume":"39","author":"Borghese","year":"2019","journal-title":"Anticancer. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"563","DOI":"10.4103\/IJPM.IJPM_1379_20","article-title":"Pure Primary Ovarian Carcinoid Tumor with Carcinoid Syndrome and Cervical Carcinoma: A Rare Concoction of Dual Primary Malignancies","volume":"64","author":"Mishra","year":"2021","journal-title":"Indian J. Pathol. Microbiol."},{"key":"ref_10","first-page":"312","article-title":"Contemporary Principles of Diagnostic and Therapeutic Management in Cervical and Ovarian Neuroendocrine Tumors","volume":"92","author":"Bidzinski","year":"2021","journal-title":"Ginekol. Pol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S623","DOI":"10.4103\/jcrt.jcrt_28_22","article-title":"Primary Neuroendocrine Tumors of Ovary: A Clinicopathological Spectrum in a Tertiary Care Hospital with Review of Literature","volume":"19","author":"Kushwaha","year":"2023","journal-title":"J. Cancer Res. Ther."},{"key":"ref_12","first-page":"128","article-title":"An Update of Neuroendocrine Tumors of the Female Reproductive System","volume":"31","author":"Kefeli","year":"2015","journal-title":"Turk. Patoloji Derg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1186\/1477-7819-12-314","article-title":"Large Cell Neuroendocrine Carcinoma of the Ovary: A Case Report and a Brief Review of the Literature","volume":"12","author":"Ki","year":"2014","journal-title":"World J. Surg. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"152619","DOI":"10.1016\/j.prp.2019.152619","article-title":"Small-Cell Carcinoma-Associated Ovarian Mucinous Carcinoma: A Case Report and Literature Review","volume":"215","author":"Wei","year":"2019","journal-title":"Pathol. Res. Pr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms","volume":"33","author":"Rindi","year":"2022","journal-title":"Endocr. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s12022-023-09789-7","article-title":"Neoplasms in Struma Ovarii: A Review","volume":"34","author":"Resta","year":"2023","journal-title":"Endocr. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Turla, A., Zamparini, M., Milione, M., Grisanti, S., Amoroso, V., Pedersini, R., Cosentini, D., and Berruti, A. (2022). Ovarian Strumal Carcinoid: Case Report, Systematic Literature Review and Pooled Analysis. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.871210"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"385","DOI":"10.4103\/IJPM.IJPM_41_20","article-title":"Synchronous Colonic Adenocarcinoma and Well-Differentiated Neuroendocrine Tumor Arising in a Mature Cystic Teratoma of Ovary\u2014Rare Presentation in a Postmenopausal Woman with Literature Review","volume":"64","author":"Ayyanar","year":"2021","journal-title":"Indian J. Pathol. Microbiol."},{"key":"ref_19","first-page":"452","article-title":"Strumal Carcinoid of the Ovary\u2014Report of Two Cases and Review of Literature","volume":"83","author":"Redecha","year":"2018","journal-title":"Ceska Gynekol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.tjog.2019.05.025","article-title":"Primary Ovarian Mucinous Carcinoid Tumor: A Case Report and Review of Literature","volume":"58","author":"Hsu","year":"2019","journal-title":"Taiwan. J. Obstet. Gynecol."},{"key":"ref_21","first-page":"375","article-title":"Primary Well Differentiated Neuroendocrine Tumor of Ovary Collides with Mucinous Borderline Tumor in a Postmenopausal Female: A Report of Case and Review of Literature","volume":"109","author":"Shahid","year":"2017","journal-title":"Pathologica"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1097\/PGP.0000000000000242","article-title":"An Ovarian Carcinoid Tumor With Peptide YY-Positive Insular Component: A Case Report and Review of the Literature","volume":"35","author":"Erdenebaatar","year":"2016","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1097\/PGP.0000000000000117","article-title":"Ovarian Strumal Carcinoid Producing Peptide YY Associated with Severe Constipation: A Case Report and Review of the Literature","volume":"34","author":"Muller","year":"2015","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1136\/ijgc-2023-005063","article-title":"Neuroendocrine Neoplasms of the Ovary: A Review of 63 Cases","volume":"34","author":"Legarreta","year":"2024","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"192","DOI":"10.3109\/09513590.2013.871518","article-title":"Cushing\u2019s Syndrome Secondary to Ectopic ACTH Secretion from Carcinoid Tumor within an Ovarian Mature Teratoma: A Case Report and Review of the Literature","volume":"30","author":"Huang","year":"2013","journal-title":"Gynecol. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Koz\u0142owski, M., Nowak, K., Kordek, A., and Cymbaluk-P\u0142oska, A. (2021). Therapeutic Management of Rare Primary Ovarian Neoplasms: Carcinosarcoma, Leiomyosarcoma, Melanoma and Carcinoid. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18157819"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Georgescu, T.-A., Bohiltea, R.E., Munteanu, O., Furtunescu, F., Lisievici, A.-C., Grigoriu, C., Gherghiceanu, F., Vl\u0103d\u0103reanu, E.M., Berceanu, C., and Ducu, I. (2021). Emerging Therapeutic Concepts and Latest Diagnostic Advancements Regarding Neuroendocrine Tumors of the Gynecologic Tract. Medicina, 57.","DOI":"10.3390\/medicina57121338"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13048-019-0543-z","article-title":"Pathological Features, Clinical Presentations and Prognostic Factors of Ovarian Large Cell Neuroendocrine Carcinoma: A Case Report and Review of Published Literature","volume":"12","author":"Yang","year":"2019","journal-title":"J. Ovarian Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e13394","DOI":"10.1111\/jne.13394","article-title":"Small-Cell Neuroendocrine Carcinoma of the Female Genital Tract: A Comprehensive Overview","volume":"36","author":"Saraei","year":"2024","journal-title":"J. Neuroendocr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.canrad.2023.08.006","article-title":"Role of Radiotherapy in the Management of Rare Gynaecological Cancers","volume":"27","author":"Espenel","year":"2023","journal-title":"Cancer Radiother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1111\/jog.12235","article-title":"Poor Prognosis of Ovarian Cancer with Large Cell Neuroendocrine Carcinoma: Case Report and Review of Published Works","volume":"40","author":"Asada","year":"2013","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2036361320968401","DOI":"10.1177\/2036361320968401","article-title":"Gynecologic Large Cell Neuroendocrine Carcinoma: A Review","volume":"12","author":"Burkeen","year":"2020","journal-title":"Rare Tumors"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ryzhkova, D., Mitrofanova, L., Tsoy, U., Grineva, E., and Schlyakhto, E. (2022). Dual-Tracer PET\/CT Imaging to Determine Tumor Heterogeneity in a Patient with Metastatic ACTH-Secreting Neuroendocrine Neoplasm: A Case Report and Literature Review. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.958442"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/24\/8833\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T10:11:43Z","timestamp":1765879903000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/24\/8833"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,13]]},"references-count":33,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["jcm14248833"],"URL":"https:\/\/doi.org\/10.3390\/jcm14248833","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,13]]}}}